The classical biogenic amines (serotonin, norepinephrine, epinephrine, dopamine, histamine) play important roles as neurotransmitters in the central and peripheral nervous system. Deutch, A. Y. and Roth R. H. (1990) Neurotransmitters. In Fundamental Neuroscience(2nd ed.) (Zigmond, M. J., Bloom, F. E., Landis, S. C., Roberts, J. L., and Squire L. R., eds.) 193-234, Academic Press. Their synthesis and storage, as well as their degradation and reuptake after release are tightly regulated. An imbalance in the levels of biogenic amines is known to be responsible for the altered brain function under many pathological conditions. Wong, M. L. and Licinio, J. (2001) Nat. Rev. Neurosci. 2, 343-351; Carlsson, A. et al. (2001), Annu. Rev. Pharmacol. Toxicol. 41, 237-260; Tuite, P. and Riss, J. (2003), Expert Opin. Investig. Drugs 12, 1335-1352; Castellanos, F. X. and Tannock, R. (2002), Nat. Rev. Neurosci. 3, 617-628.
A second class of endogenous amine compounds, the so-called trace amines (TAs) significantly overlap with the classical biogenic amines regarding structure, metabolism and subcellular localization. The TAs include p-tyramine, β-phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines. Usdin, E. and Sandler, M. eds. (1984), Trace Amines and the brain, Dekker. Their disregulation has been linked to various psychiatric diseases like schizophrenia and depression and for other conditions like attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse and eating disorders. Lindemann, L. and Hoener, M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Branchek, T. A. and Blackburn, T. P. (2003), Curr. Opin. Pharmacol. 3, 90-97; Premont, R. T. et al. (2001), Proc. Natl. Acad. Sci. U.S.A. 98, 9474-9475.
For a long time, TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the central nervous system of humans and other mammals. Mousseau, D. D. and Butterworth, R. F. (1995), Prog. Brain Res. 106, 285-291; McCormack, J. K. et al. (1986), J. Neurosci. 6, 94-101. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by “crossreacting” with their receptor systems. Premont, R. T. et al. (2001), Proc. Natl. Acad. Sci. U.S.A. 98, 9474-9475; Dyck, L. E. (1989), Life Sci. 44, 1149-1156; Parker, E. M. and Cubeddu, L. X. (1988), J. Pharmacol. Exp. Ther. 245, 199-210. This view changed significantly with the recent identification of several members of a novel family of GPCRs, the trace amine associated receptors (TAARs). Lindemann, L. and Hoener, M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005), Genomics 85, 372-385.
There are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene). The TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment. The phylogenetic relationship of the receptor genes, in agreement with an in-depth GPCR pharmacophore similarity comparison and pharmacological data suggest that these receptors form three distinct subfamilies. Lindemann, L. and Hoener, M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005), Genomics 85, 372-385. TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via Gαs. Disregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.
It has been found that the compounds of formula I (described below) have a good affinity to the TAARs, especially for TAAR1.
The compounds as useful in the treatment or prevention of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and/or cardiovascular disorders. Preferably, the compounds are useful in the treatment or prevention of disorders of the central nervous system, for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and/or attention deficit hyperactivity disorder (ADHD).